From Vitamin K Antagonism to New Oral Anticoagulants: Basic Concepts
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Thrombosis From vitamin K antagonism to new oral anticoagulants: basic concepts S. Schulman ABSTRACT Vitamin K antagonists have been used as oral anticoagulants since 1942, but the dose is difficult to Department of Medicine, McMaster predict beween individuals and is also variable over time in most patients. The research to produce University and Thrombosis and improved, target-specific anticoagulants started with the thrombin inhibitor argatroban in 1981. This Atherosclerosis Research Institute, was followed by several injectable thrombin and factor Xa inhibitors, but the ideal drug had to be oral - Hamilton, Canada and Karolinska ly available. It was necessary to map the catalytic site in order to understand how a highly selective Institutet, Stockholm, Sweden inhibitor can be developed. Structure-activity-relationship studies with a variety of analogs were cru - cial to identify compounds that combined potency, selectivity, membrane permeability and long half- Correspondence: life. These efforts from a dozen pharmaceutical companies have now resulted in one thrombin Sam Schulman inhibitor (dabigatran) and four factor Xa inhibitors (rivaroxaban, apixaban, edoxaban and betrixaban) E-mail: [email protected] that are either already used in clinical practice or in final stages of phase III clinical trials. These drugs are orally available and do not require routine laboratory monitoring due to a predictable therapeutic dose for the majority of patients. Additional advantages of these anticoagulants are rapid onset of Hematology Education: effect, faster decrease in effect after discontinuation than with warfarin, and a lower risk for intracra - the education program for the nial bleeding. They appear to have a higher risk of lower intestinal bleeding and there is to date no annual congress of the European widely available coagulation screening test that allows drug level to be assessed for all new agents Hematology Association and no clinically available reversal agent. This review describes the evolution of these new agents by 2014;8:383-390 focusing on basic concepts. Learning goals At the conclusion of this activity, participants should be able to: - understand the drug development process of oral anticoagulants; - describe the common features of the new oral anticoagulants; - describe potential benefits of the new anticoagulants based on their pharmacological characteristics. Introduction atives have a very indirect effect by inhibiting a vitamin K reductase, which leads to decreased Vitamin K antagonists have been used for oral reduction of vitamin K 2,3-epoxide and in turn to a depletion of vitamin KH 2, and finally inadequate anticoagulation for 60 years and were initially dis - g covered in 1922. In that year, the Canadian veteri - -carboxylation of coagulation factors II, VII, IX narian Frank Schofield published in The Canadian and X, as well as of the coagulation inhibitors pro - Veterinary Record his observations on cattle with tein C and protein S and other ‘off target’ proteins a hemorrhagic disease and concluded that it was (Figure 1). This is, however, not the only reason caused by moldy sweet clover. 1 Subsequently, in for the difficulty in predicting the inter- and intra- 1938, the agricultural biochemist Karl Paul Link individual effect of warfarin over a period of time. and co-workers at the University of Wisconsin Various factors all contribute to the fact that the crystallized 6 mg of the anticoagulant substance daily dose can vary from 0.5 mg to 20 mg between from spoilt sweet clover and synthesized patients: i) two enantiomers that are metabolized dicumarol (3,3’-methylenebis-(4 hydroxy - by different microsomal enzymes; ii) interactions coumarin)). 2 In 1942, the prophylactic and thera - with food and a large number of drugs; iii) a high peutic effect of the drug was reported in three degree of plasma protein binding (>99%) with a independent publications by Allen, Butsch and very small free and active fraction; iv) gene poly - Lehman. 3-5 Link continued his laboratory work to morphisms that affect both the rate of drug metab - develop a more potent anticoagulant and in 1948 olism (Cytochrome P450 [CYP] 2C9) and the tar - produced warfarin, the first 4 letters of which get enzyme vitamin K epoxide reductase subunit stand for the Wisconsin Alumni Research 1 (VKOR C1 ); and v) general disturbances in liver Foundation. metabolism in congestive heart failure or from thyroid hormone. Characteristics of warfarin Consequences for management of war - Warfarin soon became the most frequent farin coumarin derivative used for oral anticoagulation worldwide and still remains so today. These deriv - The resulting variability in effect of warfarin Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 383 | 19 th Congress of the European Hematology Association requires more intensive laboratory monitoring than for any plex with small peptides (D-Phe-Pro-Arg CH 2Cl) and non- other drug used long term. 6 In many countries, specific petidic molecules. Now the road was paved to design anticoagulation clinics have been organized to manage small molecules that would fit snugly into the serine pro - large numbers of these patients. Measurement of the pro - tease pocket. thrombin time is taken on average every 2-3 weeks. This incurs a burden for those patients who are working, but The prototypes also for the elderly who may be unable to visit the antico - agulation clinic or the medical laboratory. Investigation of the active site of thrombin revealed that It has, therefore, been a longstanding wish to design it contains 3 strategic pockets, the D-pocket, the P-pocket anticoagulant drugs that are orally administered but that and the S-pocket, with some alternative molecular compo - do not require laboratory monitoring. Attempts were made nents that will fit into the respective areas (Figure 1). The in the 1980s to develop such a drug. Thrombin, the last small molecules designed to fit into these pockets bind serine protease in the coagulation cascade, seemed to be reversibly, in contrast to hirudin or its analogs which bind an important specific target for anticoagulation therapy. irreversibly to the adjacent thrombin exosite 1 and in addi - With the availability of X-ray crystallography, Bode et al. tion block the active site. The reversible inhibition of the at the Max-Planck Institute for biochemistry were able to active site is, at least theoretically, an advantage that report the crystallographic 3-dimensional configuration of allows for some thrombin formation and reduced risk of the thrombin molecule reaching a resolution of 1.9Å. 7 This bleeding. Some pharmacokinetic characteristics of these revealed the configuration of the active site pocket in com - drugs are summarized in Table 1. Table 1. Characteristics of 1st-generation small-molecule thrombin inhibitors. Compound MW Ki Half-life Clearance Not orally available Argatroban 509 g/mol 40 nmol/L 20-60 min 4.4-5.8 mL/min/kg Efegatran 416 g/mol 18 nmol/L 35-150 min 5.9-6.4 mL/min/kg Inogatran 439 g/mol 15 nmol/L 60 min 5.4 mL/min/kg Napsagatran 559 g/mol 3 nmol/L 40-124 min 5.5-6.6 mL/min/kg Orally available Melagatran 430 g/mol 2 nmol/L 150-260 min * Atecegatran 497 g/mol 2-4 nmol/L 9-14 h 13 mL/min/kg MW: molecular weight; K i inhibition constant. *Clearance was correlated to creatinine clearance. Figure 1. Schematic view of the catalytic site of thrombin with a putative direct thrombin inhibitor fitting in. | 384 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 The prototype synthetic thrombin inhibitor was arga - effect; in approximately 7% of patients this only manifest - troban (MD-805) from Daiichi Seyaku (Tokyo, Japan) 8 ed as transient elevation of liver transaminases, but in a and the only one of the 1st-generation agents that became few patients it also resulted in jaundice and fatal out - approved, and this is still used for anticoagulation in come. 16 This appears to be an idiosynchratic effect heparin-induced thrombocytopenia. It is metabolized in depending on host immune response characteristics. the liver and is the only agent available for this condition Ximelagatran was, therefore, withdrawn from all trials and in patients with severe renal failure. markets in 2006. Another of the first small molecule active site inhibitors The company, which now had become Astra-Zeneca, was efegatran GYKI-14766 (D-MePhe-Pro-Arg-H), continued with a 2nd-generation oral thrombin inhibitor, which was developed in Hungary and turned out to have a atecegatran (AZD0837), again a prodrug with the active 17 slow-tight binding. 9 It was evaluated in acute coronary metabolite AR-H067637. It has the same benzamidine syndromes and a had similar effect to unfractionated group as melagatran, fitting in the S-pocket, but this mol - 10,11 ecule did not appear to cause elevation of liver transami - heparin. 18,19 Inogatran, developed by Astra Hässle (Mölndal, nases. In two phase II studies in patients with atrial fib - Sweden) was a peptidomimetic substance intended for rillation, the drug appeared safe and effective. A slow eventual oral administration but evaluated as intravenous release preparation to enable once-daily administration infusion in patients with unstable angina. 12 Inogatran was to be tested in phase III but was never started due to turned out to be inferior to heparin regarding episodes of lack of a sponsoring partner and increasing competition. ischemia and other clinical outcomes, at least in the short One additional oral thrombin inhibitor, sofigatran (MCC term. At Hoffmann-La Roche (Basel, Switzerland), the 977; Mitsubishi Tanabe Pharma, Osaka, Japan), with a petidomimetic agent napsagatran (Ro 46-6240) was devel - molecular weight of 484 d, was investigated in a phase II oped.